Genes Regulated in Neurons Undergoing Transcription-dependent Apoptosis Belong to Signaling Pathways Rather than the Apoptotic Machinery*
Journal - Journal of Biological Chemistry
Neuronal apoptosis has been shown to require de novo RNA/proteinsynthesis. However, very few genes whose expression is necessaryfor inducing apoptosis have been identified so far. To systematicallyidentify such genes, we have used genome-scale, long oligonucleotidemicroarrays and characterized the gene expression profile ofcerebellar granule neurons in the early phase of apoptosis elicitedby KCl deprivation. We identified 368 significantly differentiallyexpressed genes, including most of the genes previously reportedto be transcriptionally regulated in this paradigm. In addition,we identified several hundreds of genes whose transcriptionalregulation has never been associated with neuronal apoptosis.We used automated Gene Ontology annotation, analysis of promotersequences, and statistical tools to characterize these regulations.Although differentially expressed genes included some componentsof the apoptotic machinery, this functional category was notsignificantly over-represented among regulated genes. On theother hand, categories related to signal transduction were themost significantly over-represented group. This indicates thatthe apoptotic machinery is mainly constitutive, whereas molecularpathways that lead to the activation of apoptotic componentsare transcriptionally regulated. In particular, we show forthe first time that signaling pathways known to be involvedin the control of neuronal survival are regulated at the transcriptionallevel and not only by post-translational mechanisms. Moreover,our approach provides insights into novel transcription factorsand novel mechanisms, such as the unfolded protein responseand cell adhesion, that may contribute to the induction of neuronalapoptosis.* This work was supported by CNRS and by European Community BiotechGrant QLG3-CT-1999 00602 (to L. J.). The costs of publicationof this article were defrayed in part by the payment of pagecharges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicatethis fact. The on-line version of this article (available at http://www.jbc.org)contains Supplemental Tables 1 and 2.